Type II diabetes mellitus (T2DM) is a global epidemic. Therefore, the research is oriented in the development of selective inhibitors of the enzyme DPP-IV as a promising new treatment for the type II diabetes.
Sitagliptin (CAS Registry Number 486460-32-6. IUPAC Name: (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amin) is an anti-diabetic agent and a potent inhibitor of the DPP-IV. It is represented by the structure:

There is a constant search for improved synthetic protocols for key intermediates, in particular β-amino acid intermediates of the formula I,
for the synthesis of sitagliptin.
WO 03/004498 disclose a method for producing the carboxylic acid of the β-amino acid intermediate of the formula I, which is performed through a 2,3,5-trifluorobenzylbromide intermediate, where enantioselectivity was induced by the use of unusual dihydropyrazine chiral auxiliaries. In the last steps, diazomethane, which is an explosive reagent, and stoichoimetric amounts of silver salts are included in the synthetic protocol which are very expensive and therefore unsuitable reagents for industrial synthesis.
Other synthetic approaches include asymmetric hydrogenation of β-enamino acid intermediates. The asymmetric hydrogenation reactions are conducted in the presence of expensive metal catalysts like rhodium in combination with chiral phosphine/diphosphine ligands (WO 03/004498, Kubryl, M.; et. al. Tetrahedron Asymmetry 2006, 17, 205-209.). In some cases also expensive ruthenium metal catalysts are used (WO 09/064476, WO 04/085378, WO 05/097733, WO 06/081151, Hsiao, Y.; et. al. J. Am. Chem. Soc., 2004, 126, 9918-9919.). Hydrogenation with cheaper achiral catalysts involving a chiral derivatisation of enamines is also known (WO 04/085661).
Also known are synthetic strategies, which are based on the chemocatalytic selective reduction of 3-keto esters in the presence of ruthenium or rhodium diphosphine chiral catalysts (WO 04/087650, US 2009/0192326; US 2006/0052382; Hansen, K. B.; et. al. J. Am. Chem. Soc. 2009, 131, 8798-8804.; Hansen K. B.; et. al. Org. Process Res. Dev. 2005, 9, 634-639.).
WO 09/045507 discloses a biocatalytic approach to sitagliptin where an enantioselective step was performed using an appropriate enzymes (ketoreductase) for the asymmetric reduction of the β-carbonyl part of the molecule to form than the β-hydroxy intermediates. The transformation of the obtained chiral hydroxyl intermediates to the final sitagliptin precursors was performed via azetidinone intermediates. It is well known that this step is very difficult to establish. Disadvantages of these protocols are also: reactions at high pressures (250 psi), the use of very expensive metal chiral catalysts (Rh or Ru), low stereoselectivity and product contamination with rhodium and consequently hard purification protocols of final compound.
It has been also shown that rhodium or ruthenium asymmetric catalytic hydrogenation of β-keto esters through enamines can be replaced by the an efficient biocatalytic process using special enzymes transaminases, which improve the efficiency of sitagliptin manufacturing up to 99.95% enantiomeric excess (Savile, C. K.; et. al. Science 2010, 329, 305-309 and references cited therein). This enzymatic route features direct amination of the prochiral sitagliptin ketone to provide the enantiopure sitagliptin, followed by phosphate salt formation to provide the final sitagliptin phosphate. It is well known that enzymatic reactions offer an environmentally friendly approach to the synthesis of final molecules but on the other hand the availability and especially price of special enzymes (isolation protocols etc.) represent a inconsiderable disadvantage of a biocatalytic process. WO 09/045507 discloses protocols for the synthesis of a β-hydroxy intermediate and the β-amino acid intermediate of formula I.
There is also disclosed an intermediate of the formula II
with R3 being methyl, but no experimental procedure, no evidence and any other signs are devoted to this intermediate (WO 2010/122578). All synthetic strategies disclosed (WO 2010/122578) are experimentally complicated, involve relatively many synthetic steps and some of them are conducted under extreme reaction conditions (temperature up to −50° C.; dry conditions etc.). The efficiency and especially the selectivity of some individual synthetic steps are modest and consequently influence the lower overall yields of the process.
Liu et al. discloses an asymmetric synthesis of sitagliptin over 9-10 steps, with the overall 31% yield and 99.5% enantiomeric excess (Liu, F.; et. al. J. Chem. Res. 2010, 34, 230-232.). The synthetic strategy involving also an intermediate of formula II presents an efficient and high selective approach to sitagliptin but on the other hand offers also a lot of disadvantages. One of these disadvantages is the long and complicated 5 steps process to obtain the intermediate of the formula II.
Some other important disadvantages are: some steps are conducted under extreme conditions (−78° C.) where special equipment is also needed; the use of extremely hazardous reagents like BuLi strongly needed for performing the aza-Michael reaction under these conditions; some steps include CH2Cl2 as an volatile, toxic and especially non-industrial and non-environmentally friendly reaction medium;
Therefore, it was an object of the present invention to provide an improved, simple, cost-beneficial, industrial friendlier and environmentally friendly process for the preparation of an intermediate of formula I.
It was another object of the present invention to provide an improved process for the preparation of an intermediate of formula I starting from the intermediate of the formula II.
It was yet another object of the present invention to provide new intermediates suitable for the preparation of anti-diabetic agents, preferably sitagliptin.